Variant 19-54155349-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP2

The ENST00000221232.11(CNOT3):c.2204G>A(p.Arg735Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R735L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

CNOT3
ENST00000221232.11 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.20

Variant links:

Genes affected

CNOT3 (HGNC:7879): (CCR4-NOT transcription complex subunit 3) Involved in regulation of stem cell population maintenance. Part of CCR4-NOT complex. [provided by Alliance of Genome Resources, Apr 2022]

CNOT3 links:

LENG1 (HGNC:15502): (leukocyte receptor cluster member 1)

LENG1 links:

CNOT3 (HGNC:):

CNOT3 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a region_of_interest Repressor domain (size 92) in uniprot entity CNOT3_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in ENST00000221232.11

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-54155349-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3387818.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CNOT3. . Trascript score misZ 3.772 (greater than threshold 3.09). GenCC has associacion of gene with complex neurodevelopmental disorder, intellectual developmental disorder with speech delay, autism, and dysmorphic facies.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNOT3	NM_014516.4 linkuse as main transcript	c.2204G>A	p.Arg735Gln	missense_variant	18/18	ENST00000221232.11	NP_055331.1	O75175A0A024R4R3
LENG1	NM_024316.3 linkuse as main transcript	c.*372C>T		3_prime_UTR_variant	4/4	ENST00000222224.4	NP_077292.2	Q96BZ8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNOT3	ENST00000221232.11 linkuse as main transcript	c.2204G>A	p.Arg735Gln	missense_variant	18/18	1	NM_014516.4	ENSP00000221232.5		O75175
LENG1	ENST00000222224 linkuse as main transcript	c.*372C>T		3_prime_UTR_variant	4/4	1	NM_024316.3	ENSP00000222224.3		Q96BZ8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 18, 2021

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.33

T;T;.

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.98

M_CAP

Benign

0.056

MetaRNN

Uncertain

0.70

D;D;D

MetaSVM

Benign

-0.53

MutationAssessor

Pathogenic

3.0

M;M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-3.3

D;.;D

REVEL

Uncertain

0.30

Sift

Pathogenic

0.0

D;.;D

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

0.95

P;P;.

Vest4

0.63

MutPred

0.58

Gain of ubiquitination at K737 (P = 0.068);Gain of ubiquitination at K737 (P = 0.068);.;

MVP

0.71

ClinPred

0.99

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.87

gMVP

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over